MAVS-Mediated Pulmonary Inflammation and Injury Response During Cigarette Smoke Exposure and Influenza Viral Infection and in COPD

病毒感染对暴露在香烟烟雾(CS)中的个人有更严重的后果 比那些没有接触CS的人更多。慢性阻塞性肺疾病的急性加重导致肺功能迅速下降。 令人惊讶的是，在接触CS的个人中，夸大的病毒诱导反应背后的机制 还没有得到充分的解决。我们的研究表明，病毒会导致 CS染毒小鼠的炎症、组织破坏和肺纤维化。我们首先报道了CS的不良反应 通过线粒体抗病毒信号分子(MAV)的零突变消除暴露，MAV是关键的适配器 与线粒体外膜结合的分子，对抗病毒信号至关重要。为了进一步定义 这些反应的机制，在CS引起MAVS介导的信号转导改变的前提下，我们 已集中在CS暴露中MAVS介导的信号转导及其调控机制的失调 CS病毒暴露小鼠。 我们的研究突出了以下新的见解：(1)CS暴露导致持续性巨噬细胞 流感病毒感染后炎症和肺纤维化增加；(2)肺巨噬细胞显示 MAVS水平升高，与过度炎症、损伤和纤维化反应有关 (3)体外培养的CS-Flu肺成纤维细胞增殖明显增强，α-干扰素表达增强。 平滑肌肌动蛋白染色的应激纤维，促纤维化和促增殖的生长因子表达 转录信号；(4)MAVS介导的关键事件-的多聚体 抗病毒信号在接触CS流感的小鼠肺中显著增强；(5)COPD患者的肺 增加MAV聚集；(6)炎性小体激活、炎症和组织损伤反应 在CS流感肺中被夸大，并涉及MAV；和(7)磷酸酶和紧张素同源物(PTEN)- 诱导的假想蛋白1(PINK1)是线粒体健康的重要调节因子，起着关键的抑制作用 在调节MAVS介导的炎性小体和病理学方面。 基于这些观察，我们假设CS诱导的MAV动态平衡失调 线粒体在夸大的肺部炎症和组织损伤中起着关键的作用 在病毒感染期间在肺部观察到的反应。在目标1中，我们将描述 MAVS对线粒体、MAVS类病毒聚集和MAVS-和PINK1-的动态平衡调节 CS和流感病毒共暴露后介导的信号传导。在目标2中，我们将定义 PINK1介导的MAVS聚集对烟雾加重的病理肺结局的调节 流感病理学和PINK1增强作为一种可能的治疗方法。在目标3中，我们将描述 吸烟暴露和呼吸道病毒感染患者MAVS聚集途径的研究 这些拟议的研究将为MAV如何调节巨噬细胞-成纤维细胞提供新的见解 CS暴露与病毒感染肺部的相互作用，希望开发新的、基于发病机制的 改善COPD急性加重等疾病患者预后的治疗。

Viral infections have more severe consequences in individuals who have been exposed to cigarette smoke (CS) than in those not exposed to CS. Acute exacerbations of COPD contributes toward rapid lung function decline. Surprisingly, the mechanisms that underlie the exaggerated virus-induced responses in CS-exposed individuals have not been adequately addressed. Our studies demonstrated that viruses cause increased levels of inflammation, tissue destruction and lung fibrosis in CS exposed mice. We first reported adverse effects of CS exposure were eliminated by null mutations of mitochondrial antiviral signaling molecule (MAVS), a key adapter molecule that is bound to the mitochondrial outer membrane and essential for antiviral signaling. To further define the mechanisms of these responses, on the premise that CS causes alteration of MAVS-mediated signaling, we have focused on the dysregulation of MAVS-mediated signaling and its regulatory mechanisms in CS-exposed and CS + virus exposed mice. Our studies highlight the following novel insights: (1) CS exposure leads to persistent macrophage inflammation and increased fibrotic lung changes after influenza virus (Flu); (2) Lung macrophages show increased MAVS levels which were associated with excessive inflammatory, injury and fibrotic responses during CS+Flu; (3) Ex vivo lung-derived fibroblasts from CS+Flu have increased proliferation, expression of alpha- smooth muscle actin stained stress fibers, growth factor expression with pro-fibrotic and pro-proliferative transcriptomic signature; (4) The prion-like multimeric aggregation of MAVS, a key event in MAVS-mediated antiviral signaling, is markedly enhanced in mouse lungs exposed to CS+Flu; (5) Lungs from COPD patients have increased MAVS aggregation; (6) Inflammasomes activation, inflammatory and tissue damage responses are exaggerated in CS+Flu lungs and involves MAVS; and (7) Phosphatase and tensin homologue (PTEN)- induced putative kinase 1 (PINK1), an important regulator of mitochondrial health, plays a critical inhibitory role in regulating MAVS-mediated inflammasomes and pathology. Based on these observations, we hypothesize that CS-induced dysregulation of MAVS homeostasis on mitochondria has a critical functional role in the exaggerated pulmonary inflammation and tissue damage responses observed in the lungs during viral infection. In Aim 1, we will characterize the dysregulation of homeostatic regulation of MAVS on mitochondria, the MAVS prion-like aggregation and MAVS- and PINK1- mediated signaling after CS and influenza virus co-exposure. In Aim 2, we will define the consequences of PINK1-mediated regulation of MAVS aggregation on pathological pulmonary outcomes in smoke exacerbated influenza pathology and PINK1 augmentation as a possible therapeutic approach. In Aim 3, we will characterize MAVS aggregation pathway in patients with smoking exposure and respiratory viral infection. These proposed studies will provide new insights into how MAVS regulates macrophage-fibroblast interactions in CS exposure and virus infected lungs with the hope of developing novel, pathogenesis-based therapies to improve patient outcomes in diseases such as acute exacerbations of COPD.